CN103554075A - New method for preparing osthol analogue - Google Patents

New method for preparing osthol analogue Download PDF

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CN103554075A
CN103554075A CN201310526070.6A CN201310526070A CN103554075A CN 103554075 A CN103554075 A CN 103554075A CN 201310526070 A CN201310526070 A CN 201310526070A CN 103554075 A CN103554075 A CN 103554075A
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osthole
reaction
analogue
preparing
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CN103554075B (en
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章维华
张雅琴
刘品
徐子超
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Nanjing Agricultural University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7

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Abstract

The invention discloses a new method for preparing osthol analogue. The method comprises the steps of: directly performing methyl elimination reaction on a raw material which is natural and abundant osthol through BBr3 to obtain an intermediate of a hydrogen bromide addition product; directly performing etherification reaction on the intermediate, wherein hydrogen bromide elimination and separation for making 7-hydroxyl-8-isopentene coumarin are not required, two steps of removing hydrogen bromide and performing alkyl derivatization of 7-hydroxyl are changed into one-pot reaction. The new method for preparing osthol analogue is mild in reaction conditions, single in product, and simple for after-treatment; catalytic hydrogenation is needed in during reaction and active group isopentenyl is not decomposed; and the method is relatively simple to operate.

Description

A kind of novel method of preparing osthole analogue
Technical field
The invention belongs to the field of chemical synthesis, relate to a kind of novel method of preparing osthole analogue.
Background technology
Osthole (Osthol), has another name called Osthole (Osthol), is a kind of coumarin kind compound extracting from samphire cnidium monnieri mature fruit Fructus Cnidii (Fructus Cnidii).Research finds that osthole all has certain active function at aspects such as antiasthmatic-antitussive, antibiotic, anti-arrhythmia, osteoporosis, antimycotic, anti-AIDS, and find that osthole has the effect of desinsection, diseases prevention in agricultural, therefore becomes the study hotspot of recent domestic round the research of its main active ingredient osthole.
At present, on document about take osthole as the report of the synthetic osthole analogue of raw material a lot, the report that obtains its analogue by demethyl method mainly contains following three kinds.One: 2006 Wu of Nian， Guizhou University of method builds the loyal halfcystine/NaH of use method, take DMF as solvent, and reaction obtains 7-hydroxyl-8-isopentene group tonka bean camphor.But the method finds in experimentation, because its higher boiling point is difficult to remove from product, there is serious conditions of streaking in organic solvent DMF in column chromatography process, and the proterties that finally obtains product is oily matter.
Figure BDA0000404870490000011
Method two: the people such as the 2000 Geetha Gopalakrishnan of Nian， India Madras university pass through AlCl 3/ EtSH and AlCl 3/ DMS method is carried out demethylating reaction to osthole, and reaction finds to use AlCl 3what/EtSH method obtained is cyclization product, uses AlCl 3/ DMS can slough the methyl on 7 smoothly.But find to obtain osthole analogue in experimentation, not only reaction conditions is difficult to control, and control strict anhydrous condition, and anhydrous AlCl 3in air, be just very easy to water suction deliquescence rotten, and the yield of product 7-hydroxyl-8-isopentene group tonka bean camphor is very low.Meanwhile, in this reaction process, use sulfide, smell is more unpleasant.
Figure BDA0000404870490000021
Method three: the structure of modification of Tokyo Univ Japan to osthole, first first carries out hydrogenation reaction by the two keys on 8, and then uses BBr 3carry out demethylating reaction.This reaction not only needs high pressure, uses inflammable and explosive H 2, expensive metal catalyst, and destroyed active group isopentene group, to the fungicidal activity of product, may exert an influence.
Figure BDA0000404870490000022
Summary of the invention
The object of the invention is the above-mentioned deficiency for prior art, a kind of novel method of preparing osthole analogue is provided.
Object of the present invention can be achieved through the following technical solutions:
A novel method of preparing osthole analogue, take the osthole shown in formula I as raw material, uses BBr 3carry out demethylating reaction, obtain the osthole hydrogen bromide affixture shown in formula II, the osthole hydrogen bromide affixture shown in formula II of take obtains the osthole analogue shown in formula IV as intermediate directly carries out Williamson etherification reaction, and reaction scheme is as follows:
Figure BDA0000404870490000023
C1～3 alkyl that the alkyl or phenyl of C2～6 that the alkyl that wherein R is C2～C6, thiazolinyl, C1～3 alkoxyl group replace replaces, X is halogen.
Described R is preferred :-CH 2cH 3,-CH 2cH 2cH 3,-CH (CH 3) 2,-(CH 2) 3cH 3,-(CH 2) 4cH 3,-CH 2ph ,-CH 2cH 2cH 2br ,-CH 2cH=CH 2,-CH 2cH=CH 2cH 3or-CH 2cH 2cH 2oCH 3in any one; The preferred Br of described X.
Described demethylating reaction is preferred: take osthole as raw material, itself and magnet rotor are dropped in single port bottle, vacuumize, be filled with nitrogen, keep anhydrous and oxygen-free environment, in bottle, add anhydrous methylene chloride vibration, make material dissolution, reaction flask is placed in to the cryotrap of-78 ℃～0 ℃, in bottle, dropwise splashes into BBr 3cH 2cl 2solution, makes system temperature slowly rise to 20～35 ℃ after dripping off, react in the backward system of 3～10h and add saturated NaHCO 3solution cancellation reaction, obtains compound 8-(the bromo-3-methyl butyl of the 3-)-umbelliferone shown in formula II.
In described demethylating reaction, described BBr 3with the preferred 3～10:1 of the ratio of osthole molar weight, BBr 3cH 2cl 2solution time for adding is 0.2～1h preferably.
In described demethylating reaction, after cancellation reaction, preferably use CH 2cl 2extraction, anhydrous sodium sulfate drying, concentrating under reduced pressure, subsequent column chromatography purifying, obtains compound 8-(the bromo-3-methyl butyl of the 3-)-umbelliferone shown in formula II.
Described Williamson etherification reaction: take formula II compound 8-(the bromo-3-methyl butyl of the 3-)-umbelliferone, the K that make 2cO 3add in two-mouth bottle, under nitrogen protection, add wherein acetone, stir and make material dissolution, reflux, modus ponens III compound dropwise adds reaction system, and stopped reaction after stirring reaction 3～24h is cooled to 20～35 ℃; With sand core funnel, by reacting liquid filtering, remove potassium carbonate powder wherein, in filtrate, add 10% hydrochloric acid soln and ethyl acetate washing and extraction, the osthole analogue shown in the formula that the is IV in organic layer.
In described Williamson etherification reaction, K 2cO 3with the preferred 1～4:1 of the mol ratio of formula II compound, further preferred 1.5～2:1; The mol ratio of formula III compound and formula II compound is 1.0～10:1 preferably, further preferred 1.0～7:1.
In described Williamson etherification reaction, described organic layer anhydrous sodium sulfate drying, the filtrate decompression removing by filter after sodium sulfate is concentrated, and column chromatographic isolation and purification obtains the osthole analogue shown in formula IV.
The osthole analogue of preparing according to the novel method of preparing osthole analogue of the present invention, be respectively the 8-shown in formula II (the bromo-3-methyl butyl of 3-)-umbelliferone, 7-isopropoxy-8-isopentene group tonka bean camphor shown in formula IV-c, 7-butoxy-8-isopentene group tonka bean camphor shown in formula IV-d, 7-pentyloxy-8-isopentene group tonka bean camphor shown in formula IV-e, 7-shown in formula IV-g (3-methoxy propoxy)-8-isopentene group tonka bean camphor, 7-shown in formula IV-h (3-bromine propoxy-)-8-isopentene group tonka bean camphor, 7-allyloxy-8-isopentene group tonka bean camphor shown in formula IV-i, 7-methyl allyloxy-8-isopentene group tonka bean camphor shown in formula IV-j, structural formula is as follows respectively:
Figure BDA0000404870490000041
Beneficial effect:
It is raw material that the abundant osthole of natural origin is take in the present invention, uses BBr 3directly it is carried out to methyl elimination reaction, obtain the intermediate of hydrogen bromide affixture, this intermediate is directly carried out to etherification reaction, without carrying out dehydrobromination separation, produce 7-hydroxyl-8-isopentene group tonka bean camphor, change the hydrocarbyl derivative two-step reaction of dehydrobromination and 7 hydroxyls into one kettle way and carry out simultaneously.The preparation method of this osthole analogue, reaction conditions is gentle, and product is single, and aftertreatment is simple; Reaction does not need shortening, does not destroy active group isopentene group; Operate relatively simple.
The present invention has also synthesized a series of new osthole analogues by this preparation method.
The coumarin compound the present invention relates to, preliminary biological activity determination shows that they have certain restraining effect to Rhizoctonia solani Kuhn and fusarium graminearum, individual compound has stronger restraining effect, as compounds Ⅳ-c, IV-f, IV-i to the inhibiting rate of Rhizoctonia solani Kuhn all over 75%, compounds Ⅳ-c and IV-f reach respectively 85.4% and 92.7% to the inhibiting rate of fusarium graminearum, are the agricultural chemicals lead compounds of potential rice sheath blight disease and wheat scab.
Specific implementation method
Below in conjunction with concrete example, the present invention is described in further detail, but protection scope of the present invention is not limited to this.
The preparation of the compound 8-shown in embodiment 1 formula II (the bromo-3-methyl butyl of 3-)-umbelliferone
Figure BDA0000404870490000051
By 246.4mg(1.009mmol) osthole and magnet rotor drop in single port bottle, vacuumizes, and is filled with nitrogen, keeps anhydrous and oxygen-free environment.In bottle, add the vibration of 15mL anhydrous methylene chloride, make material dissolution.Reaction flask is placed in to the cryotrap of-78 ℃, in bottle, dropwise splashes into BBr 30.3mL(3.1mmol), within 20 minutes, drip off.After dripping off, make system temperature slowly rise to room temperature.During reaction 8h, TLC detects, and finds that raw material point almost completely disappears, and only has a product dot generation.In system, add saturated NaHCO 3solution cancellation reaction, CH 2cl 2extraction (40mL * 3), adds anhydrous sodium sulfate drying.Filter, filtrate evaporate to dryness, obtains tawny oily matter.Sherwood oil/methylene dichloride recrystallization, is cooled to solid and separates out.Suction filtration obtains (8-(the bromo-3-methyl butyl of the 3-)-umbelliferone) 232.25mg shown in white solid formula II, productive rate 84.5%, and the dry rear fusing point of surveying, fusing point is 92.6～93.3 ℃.
Characterization data: 1h NMR (400MHz, DMSO) δ 10.50 (s, 1H), 7.92 (d, J=9.4Hz, 1H), 7.39 (d, J=8.5Hz, 1H), 6.85 (d, J=8.5Hz, 1H), 6.20 (d, J=9.4Hz, 1H), 3.06 – 2.80 (m, 2H), 2.05 – 1.94 (m, 2H), 1.84 (s, 6H). 13c NMR (101MHz, CDCl 3) δ 157.74,153.30,144.18,126.33,114.58,111.99,111.66,109.37,75.74,45.99,34.01,31.55,26.67,16.55.IR (ν/cm -1): 3328.59,2968.68,2936.65,1701.96,1599.55,1569.54,1503.47,1405.43,1372.40,1305.88,1251.82,1122.08,1107.75,1059.30,1002.14,826.68.MSm/z:230 (M-Br), 229,215,201,197,187,175,146,131,115,103,91,89,77,65,58,45.
Embodiment 27-oxyethyl group-8-isopentene group tonka bean camphor
Figure BDA0000404870490000052
Take the formula II compound 217.82mg(0.7mmol that embodiment 1 makes), K 2cO 3193.5mg(1.4mmol) add in 50mL two-mouth bottle, under nitrogen protection, add wherein the acetone 20mL of new steaming, stir and make material dissolution, reflux.With syringe, measuring 0.2mL(2.7mmol) the new monobromethane steaming dropwise adds reaction system.Stirring reaction 5h, TLC monitors reaction, finds that raw material transforms completely.Question response liquid is cooled to after room temperature, adds 10% hydrochloric acid soln to regulate pH value to acid, ethyl acetate extraction and washing, organic layer anhydrous sodium sulfate drying 2h in filtrate.Remove by filter sodium sulfate, filtrate is spin-dried for, column chromatographic isolation and purification.Sherwood oil: ethyl acetate=14:1 obtains principal product, is spin-dried for to obtain white powder solid (structure is as shown in IV-a) 114.5mg, productive rate 63.3%, and the dry rear fusing point of surveying, fusing point is 90.0～92.4 ℃.
Characterization data: 1h NMR (400MHz, CDCl 3) δ 7.61 (d, J=9.5Hz, 1H), 7.27 (d, J=8.6Hz, 1H), 6.81 (d, J=8.6Hz, 1H), 6.23 (d, J=9.4Hz, 1H), 5.25 (t, J=7.4Hz, 1H), 4.17 – 4.09 (m, 2H), 3.55 (d, J=7.4Hz, 2H), 1.85 (s, 3H), 1.67 (s, 3H), 1.47 (t, J=6.9Hz, 3H). 13c NMR (101MHz, CDCl 3) δ 161.57,159.87,152.95,143.83,132.44,126.18,121.44,118.00,114.55,112.98,108.46,64.40,25.77,22.04,18.20,14.74.IR (ν/cm -1): 2973.97,2924.81,1716.65,1606.76,1560.79,1495.77,1435.28,1404.65,1278.82,1250.18,1160.52,1127.62,1113.64,1081.04,853.17,826.98.MS (m/z): 258 (M +), 243,230,215,203,175,171,147,131,123,106,91,69,58,51.
Embodiment 37-propoxy--8-isopentene group tonka bean camphor
Figure BDA0000404870490000061
In bis-mouthfuls of bottles of 50mL, drop into 0.155g formula II compound (0.5mmol), K 2cO 30.138g(1mmol), add wherein 20mL acetone, stir and make material dissolution, reflux.With syringe, measure 0.1mL(1.1mmol) 1-N-PROPYLE BROMIDE, TLC monitors reaction process, and after 12h, raw material point disappears.Question response liquid is cooled to after room temperature, in filtrate, adds 10% hydrochloric acid soln to regulate pH value to acidity, ethyl acetate extraction and washing, and organic layer spends the night with anhydrous sodium sulfate drying.The filtrate removing by filter after sodium sulfate is spin-dried for, column chromatographic isolation and purification.Sherwood oil: ethyl acetate=14:1 obtains principal product, is spin-dried for to obtain faint yellow tabular crystal (structure is as shown in IV-b) 0.120g, productive rate 88.2%, dry rear fusing point, 90.2～93.2 ℃ of the fusing points surveyed.
Characterization data: 1h NMR (400MHz, CDCl 3) δ 7.64 (d, J=9.4Hz, 1H), 7.29 (d, J=5.0Hz, 1H), 6.83 (d, J=23.6Hz, 1H), 6.24 (d, J=19.0Hz, 1H), 5.27 (t, J=7.3Hz, 1H), 4.04 (t, J=6.4Hz, 2H), 3.58 (d, J=7.3Hz, 2H), 1.98 – 1.88 (m, 2H), 1.87 (s, 3H), 1.67 (d, J=14.7Hz, 3H), 1.10 (t, J=7.4Hz, 3H). 13c NMR (101MHz, CDCl 3) δ 161.62,159.81,152.95,143.82,132.45,126.17,121.33,117.97,112.86,108.15,70.32,26.67,25.83,22.72,22.05,18.03,10.63.IR (ν/cm -1): 2926.93,2920.64,2875.80,1717.06,1608.11,1560.23,1495.24,1473.05,1431.80,1402.88,1277.50,1249.61,1158.27,1125.73,1083.03,1030.92,849.19,826.47.MS (m/z): 272 (M +), 257,229,215,187,175,159,131,115,97,83,58,45.
Embodiment 47-isopropoxy-8-isopentene group tonka bean camphor
Figure BDA0000404870490000071
Take the formula II compound 156mg(0.5mmol making), K 2cO 3138mg(1mmol) add in 50mL two-mouth bottle, under nitrogen protection, add wherein the acetone 20mL of new steaming, stir and make material dissolution, reflux.With syringe, measuring 0.1mL(1.1mmol) 2-N-PROPYLE BROMIDE dropwise adds reaction system.During reaction 16h, TLC monitors reaction, and raw material major part transforms, and stopped reaction obtains faint yellow reaction solution.Question response liquid is cooled to after room temperature, in filtrate, adds 10% hydrochloric acid soln to regulate pH value to acidity, ethyl acetate extraction and washing, organic layer anhydrous sodium sulfate drying 3h.Remove by filter sodium sulfate, filtrate is spin-dried for, column chromatographic isolation and purification.Sherwood oil: ethyl acetate=12:1 obtains principal product white powder solid (structure is as shown in IV-c) 115mg, productive rate 84.6%, dry rear fusing point, 64.1～64.8 ℃ of the fusing points surveyed.
Characterization data: 1h NMR (400MHz, CDCl 3) δ 7.63 (d, J=9.4Hz, 1H), 7.28 (d, J=8.6Hz, 1H), 6.84 (d, J=8.6Hz, 1H), 6.25 (d, J=9.4Hz, 1H), 5.27 (t, J=7.4Hz, 1H), 4.70 (m, 1H), 3.55 (d, J=7.4Hz, 2H), 1.87 (s, 3H), 1.69 (s, 3H), 1.41 (d, 3H), 1.40 (d, 3H). 13c NMR (101MHz, CDCl 3) δ 161.50,158.71,153.24,143.78,132.24,126.01,121.41,118.95,112.82,109.41,70.78,31.57,26.67,25.81,22.13,18.09,16.55.IR (ν/cm-1): 2973.13,2917.44,1720.40,1608.86,1492.91,1404.42,1375.91,1277.57,1245.93,1159.72,1117.56,1067.77,1027.04,823.53.MS (m/z): 273 (M+1), 272 (M +), 230,215,201,187,175,146,131,115,105,96,67,58,45.
Embodiment 57-butoxy-8-isopentene group tonka bean camphor
Figure BDA0000404870490000081
In bis-mouthfuls of bottles of 50mL, drop into 0.31g formula II compound (1mmol), K 2cO 30.276g(2mmol), add wherein 20mL acetone, stir and make material dissolution, reflux.With syringe, measuring 0.4mL(3.7mmol) 1-n-butyl bromide adds in reaction system, and TLC monitors reaction process, and after 5h, raw material point disappears, and reaction finishes.Question response liquid is cooled to after room temperature, in filtrate, adds 10% hydrochloric acid soln to regulate pH value to acidity, ethyl acetate extraction and washing, and organic layer spends the night with anhydrous sodium sulfate drying.The filtrate removing by filter after sodium sulfate is spin-dried for, column chromatographic isolation and purification.Sherwood oil: ethyl acetate=14:1 obtains principal product, is spin-dried for to obtain faint yellow tabular crystal (structure is as shown in IV-d) 0.217g, productive rate 76.0%, and the dry rear fusing point of surveying, fusing point is 109.8～111.5 ℃.
Characterization data: 1h NMR (400MHz, CDCl 3) δ 7.61 (d, J=9.4Hz, 1H), 7.26 (d, J=8.6Hz, 1H), 6.81 (d, J=8.6Hz, 1H), 6.23 (d, J=9.4Hz, 1H), 5.24 (t, J=8.0Hz, 1H), 4.06 (t, J=6.4Hz, 2H), 3.55 (d, J=7.3Hz, 2H), 1.88 – 1.81 (m, 2H), 1.84 (s, 3H), 1.67 (s, 3H), 1.61 – 1.44 (m, 2H), 1.00 (t, J=7.4Hz, 3H). 13c NMR (101MHz, CDCl 3) δ 161.50,159.83,152.93,143.83,132.38,126.19,121.34,117.98,112.83,108.15,68.48,31.33,26.66,25.87,22.05,19.32,18.01,13.90.IR (ν/cm -1): 2957.43,2938.84,2874.07,1720.35,1607.95,1559.63,1495.19,1402.97,1298.38,1278.38,1247.46,1157.93,1123.59,1084.50,1028.58,843.29,826.55.MS (m/z): 287 (M+1), 286 (M +), 271,243,229,215,201,187,175,159,146,134,115,97,91,69,58,45. embodiment 67-pentyloxy-8-isopentene group tonka bean camphors
Figure BDA0000404870490000082
Take the formula II compound 231mg(0.75mmol making), K 2cO 3207mg(1.5mmol) add in 50mL two-mouth bottle, under nitrogen protection, add wherein the acetone 20mL of new steaming, stir and make material dissolution, reflux.With syringe, measuring 0.5mL(4.0mmol) bromo pentane silane dropwise adds reaction system.TLC monitors reaction process, and after reaction 14h, raw material point disappears, stopped reaction.Reaction solution is cooled to room temperature.Question response liquid is cooled to after room temperature, in filtrate, adds 10% hydrochloric acid soln to regulate pH value to acidity, ethyl acetate extraction and washing, organic layer anhydrous sodium sulfate drying 3h.Remove by filter sodium sulfate, filtrate is spin-dried for, column chromatographic isolation and purification.Sherwood oil: ethyl acetate=12:1 obtains principal product, is spin-dried for to obtain colourless lobate crystallization (structure is as shown in IV-e) 0.203g, productive rate 90.8%, and the dry rear fusing point of surveying, fusing point is 65.4～67.2 ℃.
Characterization data: 1h NMR (400MHz, CDCl 3) δ 7.64 (d, J=9.4Hz, 1H), 7.30 (d, J=8.6Hz, 1H), 6.83 (d, J=8.6Hz, 1H), 6.26 (d, J=9.4Hz, 1H), 5.27 (t, J=7.3Hz, 1H), 4.07 (t, J=6.4Hz, 2H), 3.57 (d, J=7.2Hz, 2H), 1.90 (d, J=6.7Hz, 2H), 1.56 – 1.48 (m, 2H), 1.47 – 1.40 (m, 2H), 1.40 (s, 3H), 1.29 (s,, 3H), 0.97 (t, J=7.2Hz, 3H). 13c NMR (101MHz, CDCl 3) δ 161.40,159.30,152.96,143.77,136.40,132.70,128.69,128.17,127.25,126.20,121.16,118.43,113.20,108.68,70.59,25.85,22.17,18.00.IR (ν/cm -1): 2925.31,2856.37,1723.73,1609.47,1560.65,1493.53,1403.64,1279.46,1247.24,1162.30,1118.57,1080.12,1028.89,828.91.MS m/z:300[M]+, 285,257,243,229,215,201,175,162,146,131,115,91,69,55.
Embodiment 77-benzyloxy-8-isopentene group tonka bean camphor
Figure BDA0000404870490000091
Take the formula II compound 156mg(0.5mmol making), K 2cO 3138mg(1mmol) add in 50mL two-mouth bottle, under nitrogen protection, add wherein the acetone 20mL of new steaming, stir and make material dissolution, reflux.With syringe, measuring 0.4mL(3.4mmol) cylite dropwise adds reaction system.TLC monitors reaction process, and after reaction 5h, raw material point disappears, stopped reaction.Reaction solution is cooled to room temperature.Question response liquid is cooled to after room temperature, in filtrate, adds 10% hydrochloric acid soln to regulate pH value to acidity, ethyl acetate extraction and washing, organic layer anhydrous sodium sulfate drying 3h.Remove by filter sodium sulfate, filtrate is spin-dried for, column chromatographic isolation and purification.Sherwood oil: ethyl acetate=12:1 obtains principal product, is spin-dried for to obtain yellow powder shape solid (structure is as shown in IV-f) 0.1103g, productive rate 72.6%, dry rear fusing point, 81.7～84.0 ℃ of the fusing points surveyed.
Characterization data: 1h NMR (400MHz, CDCl 3) δ 7.61 (d, J=9.5Hz, 1H), 7.52 – 7.30 (m, 5H), 7.27 (d, 1H), 6.87 (d, J=8.6Hz, 1H), 6.25 (d, J=9.4Hz, 1H), 5.25 (t, J=7.3Hz, 1H), 5.19 (s, 2H), 3.60 (d, J=7.3Hz, 2H), 1.76 (s, 3H), 1.66 (s, 3H). 13cNMR (101MHz, CDCl 3) δ 161.40,159.30,152.96,143.77,136.40,132.70,128.69,128.17,127.25,126.20,121.16,118.43,113.19,108.68,70.59,25.85,22.17,18.00.IR (ν/cm -1): 2965.48,2911.03,2846.98,1716.74,1608.33,1562.12,1497.41,1398.98,1299.34,1276.80,1239.29,1159.79,1121.59,1073.21,1030.73,1008.66,835.51.MS (m/z): 303 (M+1), 277,264,248,229,213,201,187,175,145,131,123,103,91,65,58,45. embodiment 87-(3-methoxy propoxy)-8-isopentene group tonka bean camphors
In bis-mouthfuls of bottles of 50mL, drop into 0.31g formula II compound (1mmol), K 2cO 30.276g(2mmol), add wherein 20mL acetone, stir and make material dissolution, reflux.With syringe, measure 0.2mL(1.8mmol) the bromo-3-methoxy propane of 1-, TLC monitors reaction process, and after 6h, raw material point disappears, and reaction finishes.Question response liquid is cooled to after room temperature, in filtrate, adds 10% hydrochloric acid soln to regulate pH value to acidity, ethyl acetate extraction and washing, and organic layer spends the night with anhydrous sodium sulfate drying.The filtrate removing by filter after sodium sulfate is spin-dried for, column chromatographic isolation and purification.Sherwood oil: ethyl acetate=14:1 obtains principal product, is spin-dried for to obtain colourless acicular crystal (structure is as shown in IV-g) 0.249g, productive rate 82.3%, dry rear fusing point, 81.8～82.5 ℃ of the fusing points surveyed.
Characterization data: 1h NMR (400MHz, CDCl 3) δ 7.62 (d, J=9.5Hz, 1H), 7.28 (d, J=7.9Hz, 1H), 6.84 (d, J=8.6Hz, 1H), 6.24 (d, J=9.4Hz, 1H), 5.23 (t, J=6.6Hz, 1H), 4.16 (t, J=6.2Hz, 2H), 3.59 (t, J=6.1Hz, 2H), 3.55 (d, J=7.1Hz, 2H), 3.37 (s, 3H), 2.11 (p, J=6.1Hz, 2H), 1.84 (s, 3H), 1.67 (s, 3H). 13c NMR (101MHz, CDCl 3) δ 161.37,159.64,152.91,143.81,132.39,126.23,121.35,117.97,112.96,108.18,69.00,65.59,58.82,29.68,25.83,22.05,18.04.IR (ν/cm -1): 2959.07,2923.98,2882.21,1718.33,1603.62,1560.90,1497.60,1470.90,1428.07,1404.95,1280.04,1251.39,1161.82,1120.58,1092.62,1076.56,838.87.MS (m/z): 303(M+1), 302 (M +), 287,256,229,215,201,187,175,159,146,128,115,96,91,73,58,45.
Embodiment 97-(3-bromine propoxy-)-8-isopentene group tonka bean camphor
Figure BDA0000404870490000111
In bis-mouthfuls of bottles of 50mL, drop into 0.155g formula II compound (0.5mmol), K 2cO 30.138g(1mmol), add wherein 20mL acetone, stir and make material dissolution, reflux.With syringe, measure 0.3mL1,3-dibromopropane (3.0mmol), TLC monitors reaction process, and after 6h, raw material point disappears, and reaction finishes.Question response liquid is cooled to after room temperature, in filtrate, adds 10% hydrochloric acid soln to regulate pH value to acidity, ethyl acetate extraction and washing, and organic layer spends the night with anhydrous sodium sulfate drying.The filtrate removing by filter after sodium sulfate is spin-dried for, column chromatographic isolation and purification.Sherwood oil: ethyl acetate=10:1 obtains principal product, is spin-dried for to obtain blackish green chip solid (structure is as shown in IV-h) 0.139g, productive rate 79.7%, dry rear fusing point, 83.3～85.4 ℃ of the fusing points surveyed.
Characterization data: 1h NMR (400MHz, CDCl 3) δ 7.62 (d, J=9.5Hz, 1H), 7.29 (d, J=8.6Hz, 1H), 6.85 (d, J=8.6Hz, 1H), 6.25 (d, J=9.4Hz, 1H), 5.20 (t, J=8.5Hz, 1H), 4.22 (t, J=5.8Hz, 2H), 3.69 – 3.61 (m, 2H), 3.54 (d, J=7.1Hz, 2H), 2.44 – 2.32 (m, 2H), 1.83 (s, 3H), 1.68 (s, 3H). 13c NMR (101MHz, CDCl 3) δ 161.35,159.26,152.95,143.74,132.54,126.31,121.29,118.10,113.20,110.26,108.18,66.15,32.32,29.70,25.78,22.07,18.02.IR (ν/cm -1): 2971.89,1729.77,1607.02,1560.07,1496.82,1470.12,1437.51,1402.21,1281.75,1249.93,1215.10,1161.21,1122.10,1103.44,1086.27,826.74.MS m/z:352 (M+1), 335,307,295,229,213,187,175,159,149,131,115,91,69,58,45.
Embodiment 107-allyloxy-8-isopentene group tonka bean camphor
Figure BDA0000404870490000112
Take the formula II compound 103.7mg(0.33mmol making), K 2cO 369.11mg(0.5mmol) add in 50mL two-mouth bottle, under nitrogen protection, add wherein the acetone 13mL of new steaming, stir and make material dissolution, reflux.With syringe, measuring 0.1mL(1.16mmol) the new allyl bromide 98 steaming dropwise adds reaction system.Stirring reaction 3h TLC monitors reaction, finds that raw material transforms completely.Question response liquid is cooled to after room temperature, in filtrate, adds 10% hydrochloric acid soln to regulate pH value to acidity, ethyl acetate extraction and washing, organic layer anhydrous sodium sulfate drying 2h.The filtrate removing by filter after sodium sulfate is spin-dried for, column chromatographic isolation and purification.Sherwood oil: ethyl acetate=14:1 obtains principal product, is spin-dried for to obtain white plates crystal (structure is as shown in IV-i) 70.3mg, productive rate 78.8%, 97.1～98.1 ℃ of fusing points.
Characterization data: 1h NMR (400MHz, CDCl 3) δ 7.64 (d, J=9.5Hz, 1H), 7.30 (d, 1H), 6.83 (d, J=8.6Hz, 1H), 6.27 (d, J=9.4Hz, 1H), 6.08 (m, 1H), 5.46 (d, J=17.3,4.1,2.5Hz, 1H), 5.34 (d, J=10.6,1.4Hz, 1H), 5.31 – 5.23 (m, 1H), 4.67 (d, J=5.1,1.5Hz, 2H), 3.60 (d, J=7.3Hz, 2H), 1.86 (s, 3H), 1.69 (s, 3H). 13c NMR (101MHz, CDCl 3) δ 161.65,157.62,153.29,144.12,126.26,114.53,112.04,111.63,109.33,77.40,77.08,76.76,75.67,31.53,26.66,16.54.IR (ν/cm -1): 2977.86,2936.07,1723.07,1603.43,1491.04,1405.48,1370.06,1356.99,1279.70,1237.66,1181.86,1164.62,1122.26,1073.61,1039.29,1024.41,977.87,922.45,826.24.MS?m/z:270(M +),230,215,201,187,175,171,159,146,131,115,102,91,77,64,58,45.
Embodiment 117-methyl allyloxy-8-isopentene group tonka bean camphor
Figure BDA0000404870490000121
Take 0.31g(1mmol) formula II compound, 0.276g(2mmol) K 2cO 3in 100mL single port flask, add 40mL acetone that it is dissolved, magnetic agitation, condensing reflux.After sample dissolution, dripping 0.15mL(1.5mmol) methacrylic bromine is in reaction solution, and TLC monitors reaction process, finds the completely dissolve of raw material point after 6h.Question response liquid is cooled to after room temperature, in filtrate, adds 10% hydrochloric acid soln to regulate xh value is to acidity, ethyl acetate extraction and washing, and organic layer spends the night with anhydrous sodium sulfate drying.The filtrate removing by filter after sodium sulfate is spin-dried for, column chromatographic isolation and purification.Sherwood oil: ethyl acetate=14:1 obtains principal product, is spin-dried for to obtain white plates solid (structure is as shown in IV-j) 0.25g, productive rate 88.0%, and the dry rear fusing point of surveying, fusing point is 59.0～61.4 ℃.
Characterization data: 1h NMR (400MHz, CDCl 3) δ 7.61 (d, J=9.5Hz, 1H), 7.26 (d, J=8.5Hz, 1H), 6.81 (d, J=8.6Hz, 1H), 6.24 (d, J=9.4Hz, 1H), 5.25 (t, J=7.3Hz, 1H), 5.11 (s, 1H), 5.02 (s, 1H), 4.54 (s, 2H), 3.58 (d, J=7.2Hz, 2H), 1.84 (d, J=4.2Hz, 6H), 1.66 (s, 3H). 13c NMR (101MHz, CDCl 3) δ 161.42,159.28,152.92,143.82,140.25,132.66,126.13,121.30,118.19,113.18,108.50,72.25,31.54,26.71,25.85,22.10,19.42,18.06.IR (ν/cm -1): 3075.84,2969.02,2914.74,2856.07,1721.96,1608.33,1560.91,1494.63,1449.66,1403.28,1296.41,1277.96,1247.78,1157.45,1123.62,1091.11,1026.12,846.79,826.41.MS m/z:285 (M+1), 284 (M +), 255,229,213,187,175,146,123,107,81,58,53.
The restraining effect rough determination of embodiment 12 osthole analogues to Rhizoctonia solani Kuhn and fusarium graminearum
Test compound test medicine joins and in PDA substratum, makes pastille flat board by concentration designed after pilot study respectively.Measuring concentration is 50 μ g/ml, establishes without the dull and stereotyped contrast of medicine.Process identical with blank solvent amount.Each concentration is processed and is repeated 3 wares.Fungi adopts mycelial growth rate method.The previously prepared inoculated by hypha block of picking, on the PDA of different drug concentrations culture medium flat plate, is cultivated 3-6d at 25 ℃, checks colony diameter, calculates the percentage that each chemicals treatment suppresses mycelial growth, and result is as table 1.Table 1 is the inhibiting rate of each compound to Rhizoctonia solani Kuhn and fusarium graminearum.
The inhibiting rate of each compound of table 1 to Rhizoctonia solani Kuhn and fusarium graminearum
Compound number Rhizoctonia solani Kuhn Fusarium graminearum
Ⅱ 53.6% 50.0%
Ⅳ‐c 78.5% 85.4%
Ⅳ‐d 46.1% 0.12%
Ⅳ‐e 40.6% 0.06%
Ⅳ‐f 81.4% 92.7%
Ⅳ‐g 46.8% 18.3%
Ⅳ‐h 59.7% 21.3%
Ⅳ‐i 77.9% 17.6%
Ⅳ‐j 32.6% 15.2%
Upper table 1 shows, under experimental concentration (50 μ g/ml), each compound all has inhibition in various degree active to Rhizoctonia solani Kuhn and fusarium graminearum, wherein compound Ⅳ ?c, Ⅳ ?f, Ⅳ ?i to the inhibiting rate of Rhizoctonia solani Kuhn all over 75% Ⅳ ?c He Ⅳ ?f the inhibiting rate of fusarium graminearum is reached respectively to 85.4% and 92.7%, illustrating that these compounds have stronger restraining effect to Rhizoctonia solani Kuhn and fusarium graminearum, is the potential primer of rice sheath blight disease and wheat scab.

Claims (10)

1. a novel method of preparing osthole analogue, is characterized in that take that the osthole shown in formula I is as raw material, uses BBr 3carry out demethylating reaction, obtain the osthole hydrogen bromide affixture shown in formula II, the osthole hydrogen bromide affixture shown in formula II of take obtains the osthole analogue shown in formula IV as intermediate directly carries out Williamson etherification reaction, and reaction scheme is as follows:
Figure FDA0000404870480000011
C1～3 alkyl that the alkyl or phenyl of C2～6 that the alkyl that wherein R is C2～C6, thiazolinyl, C1～3 alkoxyl group replace replaces, X is halogen.
2. the novel method of preparing osthole analogue according to claim 1, is characterized in that described R is independently selected from :-CH 2cH 3,-CH 2cH 2cH 3,-CH (CH 3) 2,-(CH 2) 3cH 3,-(CH 2) 4cH 3,-CH 2ph ,-CH 2cH 2cH 2br ,-CH 2cH=CH 2,-CH 2cH=CH 2cH 3or-CH 2cH 2cH 2oCH 3in any one; Described X is Br.
3. the novel method of preparing osthole analogue according to claim 1 and 2, it is characterized in that described demethylating reaction: take the osthole shown in formula I as raw material, itself and magnet rotor are dropped in single port bottle, vacuumize, be filled with nitrogen, keep anhydrous and oxygen-free environment, in bottle, add anhydrous methylene chloride vibration, make material dissolution, reaction flask is placed in to the cryotrap of-78 ℃～0 ℃, in bottle, dropwise splash into BBr 3, after dripping off, make system temperature slowly rise to 20～35 ℃, react in the backward system of 3～10h and add saturated NaHCO 3solution cancellation reaction, obtains the osthole hydrogen bromide affixture shown in formula II: 8-(the bromo-3-methyl butyl of 3-)-umbelliferone.
4. the novel method of preparing osthole analogue according to claim 3, is characterized in that described BBr 3with the ratio of osthole molar weight be 3～10:1, BBr 3cH 2cl 2solution time for adding is 0.2～1h.
5. the novel method of preparing osthole analogue according to claim 3, is characterized in that, after cancellation reaction, using CH 2cl 2extraction, anhydrous sodium sulfate drying, concentrating under reduced pressure, subsequent column chromatography purifying, obtains compound 8-(the bromo-3-methyl butyl of the 3-)-umbelliferone shown in formula II.
6. the novel method of preparing osthole analogue according to claim 1 and 2, is characterized in that described Williamson etherification reaction: take formula II compound 8-(the bromo-3-methyl butyl of the 3-)-umbelliferone, the K that make 2cO 3add in two-mouth bottle, under nitrogen protection, add wherein acetone, stir and make material dissolution, reflux, modus ponens III compound dropwise adds reaction system, and stopped reaction after stirring reaction 3～24h is cooled to 20～35 ℃; With sand core funnel, by reacting liquid filtering, remove potassium carbonate powder wherein, in filtrate, add 10% hydrochloric acid soln and ethyl acetate washing and extraction, the osthole analogue shown in the formula that the is IV in organic layer.
7. the novel method of preparing osthole analogue according to claim 6, is characterized in that K 2cO 3with the mol ratio of formula II compound be 1～4:1, the mol ratio of formula III compound and formula II compound is 1.0～10:1.
8. the novel method of preparing osthole analogue according to claim 7, is characterized in that K 2cO 3with the mol ratio of formula II compound 8-(the bromo-3-methyl butyl of 3-)-umbelliferone be 1.5～2:1; The mol ratio of formula III compound and formula II compound is 1.0～7:1.
9. the novel method of preparing osthole analogue according to claim 6, it is characterized in that described organic layer anhydrous sodium sulfate drying, the filtrate decompression removing by filter after sodium sulfate is concentrated, and column chromatographic isolation and purification obtains the osthole analogue shown in formula IV.
10. the osthole analogue of preparing according to the novel method of preparing osthole analogue claimed in claim 1, the compound that it is characterized in that synthesized is respectively the 8-shown in formula II (the bromo-3-methyl butyl of 3-)-umbelliferone, 7-isopropoxy-8-isopentene group tonka bean camphor shown in formula IV-c, 7-butoxy-8-isopentene group tonka bean camphor shown in formula IV-d, 7-pentyloxy-8-isopentene group tonka bean camphor shown in formula IV-e, 7-shown in formula IV-g (3-methoxy propoxy)-8-isopentene group tonka bean camphor, 7-shown in formula IV-h (3-bromine propoxy-)-8-isopentene group tonka bean camphor, 7-allyloxy-8-isopentene group tonka bean camphor shown in formula IV-i, 7-methyl allyloxy-8-isopentene group tonka bean camphor shown in formula IV-j, structural formula is as follows respectively:
Figure FDA0000404870480000021
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CN111732565A (en) * 2020-07-28 2020-10-02 遵义医科大学 Osthole ester compound and application thereof
CN111808062A (en) * 2020-07-28 2020-10-23 遵义医科大学 Osthole sulfonate compound and application thereof
CN114621173A (en) * 2020-12-10 2022-06-14 上海医药工业研究院 Preparation method and intermediate of isoamylene heterocyclic compound

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Publication number Priority date Publication date Assignee Title
CN111732565A (en) * 2020-07-28 2020-10-02 遵义医科大学 Osthole ester compound and application thereof
CN111808062A (en) * 2020-07-28 2020-10-23 遵义医科大学 Osthole sulfonate compound and application thereof
CN111732565B (en) * 2020-07-28 2022-09-13 遵义医科大学 Osthole ester compound and application thereof
CN111808062B (en) * 2020-07-28 2022-09-13 遵义医科大学 Osthole sulfonate compound and application thereof
CN114621173A (en) * 2020-12-10 2022-06-14 上海医药工业研究院 Preparation method and intermediate of isoamylene heterocyclic compound

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